Risk Of Colorectal Adenoma Recurrence Research Articles

The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma

Existing studies suggest that metformin lowers the risk and mortality of colorectal cancer. However, the effect of metformin on the suppression and prevention of colorectal adenomas is not clear. The aim of this study was to evaluate the effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. Among 423 diabetic patients who underwent surveillance colonoscopy after resection of colorectal adenoma between 2005 and 2011, 257 patients were retrospectively reviewed. The patients were divided into two groups: one group comprising 106 patients who took metformin and another group comprising 151 patients who did not take metformin. The clinical characteristics, colorectal adenoma recurrence, and valuable factors for adenoma recurrence were analyzed. At surveillance colonoscopy after colonoscopic polypectomy for adenoma, 38 patients (35.8%) exhibited colorectal adenoma among 106 patients who took metformin, compared with 85 patients (56.3%) with colorectal adenoma among 151 patients who did not take metformin (odds ratio 0.434, 95% confidence interval 0.260-0.723, P=0.001). Multivariate Cox analysis showed that metformin was associated with decreased recurrence of colorectal adenoma (hazard ratio 0.572, 95% confidence interval 0.385-0.852, P=0.006) in diabetic patients with previous colorectal adenoma. The cumulative probability of colorectal adenoma recurrence was significantly lower in the metformin group than in the non-metformin group (P=0.001). Metformin use in diabetic patients with previous colorectal adenoma is associated with a lower risk of colorectal adenoma recurrence.

Dietary Inflammatory Index and Risk of Colorectal Adenoma Recurrence: A Pooled Analysis

ABSTRACTNo studies have evaluated the association between the dietary inflammatory index (DII) and colorectal adenoma recurrence. DII scores were calculated from a baseline food frequency questionnaire. Participants (n = 1727) were 40–80 years of age, enrolled in two Phase III clinical trials, who had ≥1 colorectal adenoma(s) removed within 6 months of study registration, and a follow-up colonoscopy during the trial. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). No statistically significant associations were found between DII and odds of colorectal adenoma recurrence [ORs (95% CIs) = 0.93 (0.73, 1.18) and 0.95 (0.73, 1.22)] for subjects in the second and third DII tertiles, respectively, compared to those in the lowest tertile (Ptrend = 0.72). No associations were found for recurrent colorectal adenoma characteristics, including advanced recurrent adenomas, large size, villous histology, or anatomic location. While our study did not support an association between a proinflammatory diet and colorectal adenoma recurrence, future studies are warranted to elucidate the role of a proinflammatory diet on the early stages of colorectal carcinogenesis.

Abstract 1739: Calcium to magnesium intake ratio and colorectal carcinogenesis, results from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial

Abstract Background A recent randomized trial found no effect of calcium supplementation on reducing risk of colorectal adenoma recurrence. However, the role of calcium in carcinogenesis is yet unconfirmed. An earlier trial found calcium treatment only reduced recurrence when the baseline calcium: magnesium intake ratio was <2.6. Nor is it clear whether calcium intake is differentially related to risks of different stages of colorectal carcinogenesis (incident adenoma, adenoma recurrence and incident colorectal cancer). Further, it is unclear if calcium intake or supplementation confers additional protection against incident colorectal cancer in individuals receiving endoscopic screenings. To address these important scientific inquiries, we have conducted analyses within the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Methods The PLCO is a large, multicenter, population-based randomized trial designed to determine the effects of screening on cancer-related mortality with a median of 12.5 years of follow up. We evaluated the associations between calcium intake and the risks of incident colorectal adenoma (1,147 cases), recurrent adenoma (855 cases) and incident colorectal cancer (697 and 578 cases in intervention and control arms, respectively) among 108,563 PLCO participants aged 55 to 74 years. Odds ratios (OR) and 95% confidence intervals (95%CIs) for incident adenoma and recurrent adenoma, and hazard ratios (HR) and 95%CIs for colorectal cancer incidence were calculated using unconditional logistic regression models and Cox proportional hazard models after adjusting covariates. Results Compared to low calcium intake (<600 mg/day), higher intakes of calcium were not related to a reduced risk of incidence adenoma, but significantly associated with a reduced risk of advanced/multiple adenomas (p for trend, <0.05). Further, the significant inverse association only appeared when calcium:magnesiuim intake ratios between 1.7 and 2.5. No significant association was observed between Ca intake and risk of adenoma recurrence. In the control arm, we found, compared to low calcium intake, higher intakes of calcium were associated with significantly reduced risks of incident colorectal cancer, primarily distal cancer. Again, we found the inverse association may primarily appear in those with calcium:magnesiuim intake ratios between 1.7 and 2.5. In contrast, in the intervention arm (i.e. screening with flexible sigmoidoscopy), overall, we did not find any significant associations. Conclusion Intake of calcium may be more strongly related to reduced risks of incident advanced/multiple adenoma and incident colorectal cancer among those without active screening with flexible sigmoidoscopy than to recurrent adenoma and incident colorectal cancer risks among those with active screening with flexible sigmoidoscopy. Citation Format: Jing Zhao, Xiangzhu Zhu, Martha J. Shrubsole, Todd L. Edwards, Edward L. Giovannucci, Wei Zheng, Qi Dai, PLCO Project Team. Calcium to magnesium intake ratio and colorectal carcinogenesis, results from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1739.

Abstract A21: A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index

Abstract Background: Despite advances in colorectal cancer (CRC) screening, early detection, and treatment, CRC remains the 2nd most common cancer cause of death in the U.S.. Obesity is increasing in incidence in the U.S., and has been implicated in colorectal adenoma (CRA) risk, risk of CRA recurrence, and risk of CRC. Obese patients with history of CRA are a high-risk group that may benefit from novel CRC prevention strategies. There is early evidence for reduced cancer mortality among metformin users. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice, as evidenced by metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPk, decreased ratio of pmTOR/mTOR, and decreased ratio of pS6Ser235/S6Ser235 in polyp specimens. We hypothesized that metformin would affect colorectal tissue S6Ser235 similarly in humans, targeting obese patients with recent history of CRAs as a high-risk group. Methods: A phase IIa clinical biomarker trial was conducted across 3 clinical sites via the NCI-funded Southern California Chemoprevention Program. Eligible participants included non-diabetic, obese patients (BMI >30) with history of colorectal adenoma within the past 3 years, age ≥ 35 years and ≤ 80 years. All patients received an upward titration of metformin over 3 weeks to 1000mg po bid, which was continued until the end-of-study (EOS) at 12 weeks. Rectal mucosa biopsies were obtained at baseline (BL) and at time of EOS endoscopy. Tissue S6Ser235 immunostaining was analyzed in a blinded fashion by the study pathologist using Histo Score (HScore) analysis. A paired t-test was used to examine the effect of metformin on activated S6serine235 (i.e., the ratio of pS6serine235/ S6serine235). Results: 45 patients were consented to achieve 32 eligible subjects. 4 subjects were removed from study due to Adverse Events (1 SAE, unrelated). In order of frequency, the most common AEs were diarrhea, cramping, flatulence, nausea, stomach pain; 80% of participants had Grade 1 AE, 27% had grade 2 AE. Mean (SD) weight and body mass index at BL were 105.2 (17.42) kg and 34.9 (5.57) respectively. Weight did not significantly differ over the course of the study. Glucose levels at EOS did not significantly differ from BL. Vitamin B12 levels were significantly reduced at EOS vs. BL (-46.7 pg/mL, 95% CI -73.2 to -20.2). Comparing EOS to BL tissue S6Ser235 by IHC HScore analysis, no significant differences were observed. Mean (SD) Hscore at BL was 1.1 (0.57) and 1.1 (0.51) at EOS. Median HScore change was 0.032 (p=0.77). Conclusions: Among obese CRA patients, 12 weeks of oral metformin 1000mg twice daily does not reduce pS6 levels in the rectal mucosa. Other potential mechanisms of action have not yet been analyzed. Data from this clinical trial indicate that metformin can be used safely in a non-diabetic population. Further research is needed to determine what effects, if any, metformin has on the target tissue of origin (colorectum) relevant to colorectal carcinogenesis if metformin is to be pursued as a CRC chemopreventive agent. Citation Format: Jason A. Zell, Christine E. McLaren, Timothy R. Morgan, Michael J. Lawson, Sherif Rezk, Gregory C. Albers, Wen-Pin Chen, Joseph C. Carmichael, Luz Rodriguez, Eva Szabo, Leslie Ford, Michael Pollak, Frank L. Meyskens. A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A21.

Abstract 1888: Calcium, magnesium, and vitamin D metabolites in colorectal adenoma prevention

Abstract In addition to the synergistic interaction between calcium and vitamin D observed in many previous studies, a recent study found that magnesium may also modify the association between serum 25-hydroxyvitamin D (25D) and risk colorectal cancer mortality. However, the study was unable to include the biologically active form of vitamin D, 1α,25-dihydroxyvitamin (1,25D), a critical component of calcium homeostasis. Both 1,25D and its precursor metabolite 25D are associated with increased risk of colorectal neoplasia when circulating concentrations are low. Furthermore, no study has investigated whether magnesium may also modify the association between serum vitamin D and risk of colorectal adenoma recurrence. We therefore conducted logistic regression analysis to evaluate the relationship between circulating vitamin D metabolites concentrations and risk of colorectal adenoma recurrence stratified by intake tertiles of magnesium or calcium, among 878 participants from the ursodeoxycholic acid randomized trial for colorectal adenoma prevention. Tertiles were created for all continuous exposure variables and all models were mutually adjusted for either magnesium or calcium, respectively. Although circulating 25D levels were not significantly associated with risk, those with 1,25D levels within the middle tertile were at significantly reduced risk of adenoma recurrence (OR = 0.68, 95% CI: 0.48-0.95). In stratified analysis by tertile of magnesium or calcium intake, we found higher 1,25D concentrations were associated with reduced risks of adenoma recurrence only for those with mean magnesium intake around the Recommended Dietary Allowance (RDA; i.e. 319 mg/day), particularly for proximal colorectal adenoma recurrence, with an OR of 0.48 (95% CI: 2.25-0.89) for the highest tertile of 1,25D compared to the lowest (p for trend, 0.02). Also, we found circulating 1,25D concentrations significantly interacted with intake of calcium in relation to risk of proximal colorectal adenoma recurrence (p for interaction, 0.01); and the inverse association between 1,25D and risk may primarily appeared in those who had intake of calcium close to or above Dietary Reference Intake (DRI) level (i.e. 1000 mg/day). No statistically significant interactions were observed for circulating 25D concentrations. Few studies have evaluated the role of 1,25D in colorectal adenoma recurrence or interactions with intake of calcium, and this is the first to examine the interaction between 1,25D with intake of magnesium. These results support the importance of interactions between calcium and magnesium homeostasis with the vitamin D endocrine system in the development of colorectal neoplasia; however, continued work, particularly large-scale studies, is necessary to replicate the finding and understand the cellular mechanism driving these population-level associations as well as applications to colorectal neoplasia prevention. Citation Format: Elizabeth A. Hibler, Peter W. Jurutka, Qi Dai, Christine L. Sardo Molmenti, Elizabeth T. Jacobs. Calcium, magnesium, and vitamin D metabolites in colorectal adenoma prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1888. doi:10.1158/1538-7445.AM2015-1888

Abstract 4584: VDR genotype modifies vitamin D efficacy for colorectal adenoma prevention in a randomized controlled trial

Abstract Objective: Although epidemiological and pre-clinical research suggests that vitamin D and calcium supplementation reduce colorectal carcinogenesis, we found that they had no effect on risk of colorectal adenoma recurrence in a recently completed randomized controlled trial (Vitamin D/Calcium Polyp Prevention Study, NCT00153816). We now examine whether the effect of supplementation may be modified by common genetic variants in vitamin D and calcium pathway genes previously associated with 25-hydroxyvitamin D levels or other health outcomes. Methods: 41 candidate single nucleotide polymorphisms (SNPs) in 7 genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR and CASR) were genotyped in non-Hispanic white trial participants (N = 1,676). All had at least one adenoma at a baseline colonoscopy and were randomized to treatment with vitamin D3 (1000 IU/day), calcium (1200 mg/day), both or placebo in a modified 2×2 factorial design. Participants were followed until a subsequent colonoscopy 3 or 5 years later and assessed for the presence of at least one adenoma or advanced adenoma (adenoma ≥1 cm, or with >25% villous histology and/or high-grade dysplasia, or cancer). Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were used to estimate genotype effects, treatment effects and interactions. To account for multiple testing, based on the effective number of independent SNPs, statistical significance was defined as p<0.002. Results: VDR SNP rs731236 (Taq1, minor allele frequency 0.39) statistically significantly modified the effect of vitamin D3 treatment on advanced adenomas (interaction RR = 0.49, 95% CI = 0.31-0.76, P = 0.001) but not on any adenoma (interaction RR = 0.94, 95% CI = 0.80-1.11, P = 0.48). Among participants (N = 249, 15%) with the homozygous variant genotype, the risk of an advanced adenoma was 15.2% among those randomized to placebo, and 3.2% among those randomized to vitamin D; a risk reduction of 78% for vitamin D supplementation (RR = 0.22, 95% CI = 0.08-0.63, P = 0.005). In contrast, among participants with one or more wild type allele (N = 1400, 85%), the risk of an advanced adenoma was 8.8% among those randomized to placebo, and 10.5% among those randomized to vitamin D; an apparent risk increase of 19% for vitamin D supplementation (RR = 1.19, 95% CI = 0.86-1.64, P = 0.3). Several other VDR SNPs in linkage disequilibrium with rs731236 had borderline statistically significant interactions. However, there were only nominally statistically significant (P<0.05) interactions of SNP genotypes with calcium treatment on adenoma outcomes. Conclusions: Our results suggest that the effect of vitamin D3 supplementation on colorectal carcinogenesis depends on common genetic variants in VDR, with a 78% reduction in risk of advanced adenomas in individuals with the rs731236 homozygous variant genotype, and no benefit in individuals with one or more wild type alleles. Note: This abstract was not presented at the meeting. Citation Format: Elizabeth L. Barry, Leila A. Mott, Judith R. Rees, Dennis J. Ahnen, Roberd M. Bostick, Robert S. Bresalier, Douglas J. Robertson, Robert W. Summers, John A. Baron. VDR genotype modifies vitamin D efficacy for colorectal adenoma prevention in a randomized controlled trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4584. doi:10.1158/1538-7445.AM2015-4584

Sedentary behavior is associated with colorectal adenoma recurrence in men.

The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between physical activity and colorectal adenoma recurrence. Pooled analyses from two randomized, controlled trials included 1,730 participants who completed the Arizona Activity Frequency Questionnaire at baseline, had a colorectal adenoma removed within 6 months of study registration, and had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior, light-intensity physical activity, and moderate-vigorous physical activity on colorectal adenoma recurrence. No statistically significant trends were found for any activity type and odds of colorectal adenoma recurrence in the pooled population. However, males with the highest levels of sedentary time experienced 47% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.23 (0.88, 1.74), 1.41 (0.99, 2.01), and 1.47 (1.03, 2.11), respectively (p(trend) = 0.03). No similar association was observed for women. This study suggests that sedentary behavior is associated with a higher risk of colorectal adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway.

Abstract A48: Sedentary behavior is associated with colorectal adenoma recurrence in men

Abstract The association between physical activity and colorectal adenoma is equivocal. This study was designed to assess the relationship between various physical activity types and colorectal adenoma recurrence in a pooled sample of participants from the Wheat Bran Fiber and Ursodeoxycholic Acid phase III clinical trials with available data from the baseline Arizona Activity Frequency Questionnaire and a follow-up colonoscopy (n=1,730). Logistic regression modeling was used to estimate the relationship between sedentary, recreational, and household activity on colorectal adenoma recurrence overall and stratified by gender. No statistically significant associations were found between any activity type and colorectal adenoma recurrence overall however, males with the highest sedentary time demonstrated a statistically significant 45% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary time, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.31 (0.93, 1.84), 1.47 (1.04, 2.09) and 1.45 (1.02, 2.06) respectively (P trend=0.03). In males, those with low recreational activity and high sedentary time was also associated with greater risk for recurrent adenoma, with an OR (95% CI) of 1.41(1.00-2.00) for high sedentary time/low recreational activity compared to the reference group (low sedentary time/low recreational activity). Our results suggests that sedentary time is associated with a higher risk of colorectal adenoma recurrence among men, supporting a role for sedentary lifestyle in the early stages of carcinogenesis. Efforts to intervene on sedentary time should be evaluated as a method for reducing recurrent adenomas. Citation Format: Christine L. Sardo, Erin L. Ashbeck, Elizabeth A. Hibler, Denise Roe, Robin B. Harris, Martin Cisneroz, Peter Lance, Maria Elena Martinez, Cynthia A. Thomson, Patricia A. Thompson, Elizabeth T. Jacobs. Sedentary behavior is associated with colorectal adenoma recurrence in men. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A48.

Short- and long-term risk of colorectal adenoma recurrence among whites and blacks

It is unclear whether the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility. To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenoma. Secondary analysis of the Polyp Prevention Trial (PPT) data. United States. Patients were 1668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a posttrial, passive Polyp Prevention Trial Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy. Recurrence and location of the adenoma and advanced adenoma by race-ethnicity during PPT and cumulative recurrence over a mean follow-up of 8.3 years (range, 4.9-12.4 years) among PPT-CFS enrollees. Blacks had similar risk of recurrence of adenoma (39.2% vs 39.4%; incidence risk ratio [RR] = .98; 95% CI, .80-1.20) and advanced adenoma (8.5% vs 6.4%; RR = 1.18; 95% CI, .68-2.05) as whites at the end of PPT. Recurrence risk did not differ by colon subsite. Among PPT-CFS enrollees, the cumulative recurrence rate over a maximal follow-up period of 12 years was similar for blacks and whites for adenoma (67.3% vs 67.0%; RR = 1.01; 95% CI, .84-1.21) and advanced adenoma (14.5% vs 16.9%; RR = 1.03; 95% CI, .60-1.79). There were few blacks in the long-term follow-up study. Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity.

CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment

CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment

CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment

The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L). We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs). Multiplicative interactions terms were used to assess effect modification. CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29% (RR=1.29, 95% CI 1.09-1.51) for ≥1 variant allele (CYP2C9*2 or *3) and 47% (RR=1.47, 95% CI 1.19-1.83) for ≥1 CYP2C9*3 allele. The risk for advanced lesions or multiple (≥3) adenomas was increased by 64% (RR=1.64, 95% CI 1.18-2.28) for ≥1 variant allele (CYP2C9*2 or *3) and 79% (RR=1.79, 95% CI 1.16-2.75) for ≥1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26% (RR=1.26, 95% CI 0.99-1.58) for former smokers and 60% (RR=1.60, 95% CI 1.19-2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ≥1 variant allele (CYP2C9*2 or *3) (p (interaction)=0.04). Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants.

Su1043 Prognostic Significance of Socio-Economic Deprivation in Upper Gastrointestinal Cancer

Background: Blacks suffer a disproportionately higher incidence of and mortality from colorectal cancer in the United States. It is unclear if this public health problem is due to an increased biological susceptibility. No prospective study has evaluated differences in postpolypectomy recurrence risk by race. Aim: To examine the prevalence, recurrence and the location of colorectal neoplasia by race during a four-year follow-up in the Polyp Prevention Trial (PPT). Methods: The PPT was a 4-year, multicenter, randomized controlled trial which evaluated the effect of a low fat, high fiber, fruits and vegetable diet on the risk of colorectal adenoma recurrence. A total of 1,821 participants, which included 1,668 (91.6%) whites and 153 (8.4%) blacks, had information on location of colorectal adenoma at baseline and underwent end-of-trial colonoscopy 4 years later. We used Poisson regression models to evaluate the association between race and advanced adenoma (defined as an adenoma that is 1 cm or more in size, or with villous component or high grade dysplasia) at baseline and recurrent adenoma and advanced adenoma at 4 years. Results: Black and white participants did not differ on mean age (60.8 versus 61.3 years; P value = 0.53) or sex (66.7% versus 64.0% male; P value = 0.52). At baseline, blacks had higher prevalence of any advanced adenoma compared to whites (44.4% versus 37.0%; P value = 0.07) and proximal advanced adenoma (14.4% versus 8.8%; P value = 0.02); but not distal advanced adenoma (32.0% versus 29.9%, P value = 0.58). At the year 4 examination, 717 (39.4%) had adenoma recurrence and 120 (6.6%) had advanced adenoma recurrence. Blacks were as likely as whites to have any adenoma and advanced adenoma recurrence after adjusting for age, sex, body mass index, use of non steroidal anti-inflammatory drugs, smoking and family history of colorectal cancer (Table). There was no difference in adenoma recurrence by location. Conclusions: Despite higher prevalence of advanced adenoma at baseline, blacks have similar colorectal neoplasia recurrence risk as whites. Our study does not provide any evidence to support more frequent surveillance for blacks with personal history of adenoma as an intervention to reduce colorectal cancer disparity. The risk of adenoma and advanced adenoma recurrence by race

Abstract 1882: Short- and long-term risk of adenoma recurrence with cigarette smoking: An analysis of the Polyp Prevention Trial and Continued Follow-Up Study

Abstract Background: Prospective studies have evaluated the association between cigarette smoking and colorectal adenoma recurrence within 4 years of follow-up, a relatively short duration. We sought to examine short- and long-term risk of adenoma recurrence in association with cigarette smoking among participants in the Polyp Prevention Trial (PPT), a multicenter, randomized controlled trial that evaluated the effect of a low fat, high fiber, fruits and vegetable diet on the risk of colorectal adenoma recurrence. Methods: A cohort of 774 participants with colorectal adenoma completed a baseline questionnaire including tobacco use and completed the 4-year trial during which they underwent colonoscopy at 1 year and 4 years after enrollment. After the trial was completed, these participants consented to passive follow-up in the Continued Follow-up Study (CFS) during which the colonoscopy reports subsequent to the trial were collected and analyzed. We defined adenoma recurrence as any adenoma detected after the baseline colonoscopy. We used Poisson regression models to evaluate risk of adenoma recurrence up to 4 years (short-term) and up to 12 years of follow-up (long-term). Results: At baseline, 461 (59.6%) participants had a history of smoking: 379 (49.0%) former smokers and 82 (10.6%) current smokers. Mean age of the patients was 59.6 years and 66.2% were males. The mean total duration of follow-up was 8.4 years (range 4.9 – 12.4 years). When compared with never smokers, there was no association between cigarette smoking and adenoma recurrence with either short- or long-term follow-up (Table). Conclusions: Cigarette smoking is not associated with adenoma recurrence in the short- or the long-term. Table: Relative Risk (RR) and 95% confidence interval (CI) for adenoma recurrence during short-term and long-term follow-up according to baseline smoking status Models were adjusted for age, sex, NSAIDs use, BMI and family history of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2011-1882

Folic acid supplementation in prevention of colorectal adenoma recurrence: a meta-analysis

Objective To evaluate the role of folic acid supplementation in prevention of colorectal adenoma recurrence. Methods Weconducted computer search of the Cochrane Central Register of Clinical Trails,Pubmed,Embase,CBMdisc and CNKI. Hand search of relevant journals and conference proceedings was also conducted. Based on the predefined inclusion and exclusion criteria,randomized controlled trials( RCT) about folic acid in treatment of patients after adenoma resection were included in the present study. After evaluating the quality of studies,meta-analyses were performed by RevMan 5. 0. 24 software for the pooled recurrence risks of colorectal adenoma and progressive colorectal adenoma. Results A total of 6 RCT studies,including 2,002 patients,were enrolled in this study. The results of meta-analysis showed that the recurrence risks of colorectal adenomas were not significantly different between folic acid supplementation and placebo groups [RR =0. 97,95% CI( 0. 79,1. 19) ,P = 0. 76]; but there were significant differences in the risks of progressive adenomas between the two groups[RR = 1. 33,95% CI ( 1. 01,1. 74) ,P = 0. 04]; and this effect of folic acid supplementation appeared when 1 mg/d folic acid supplementation was applied for ≥3 years [RR = 1. 49,95% CI( 1. 07,2. 09) ,P = 0. 02]. Conclusion Folic acid supplementation fails to reduce the risk of colorectal adenoma recurrence,and it might increase the recurrence risk of advanced adenoma.

M1177 Risk of Colorectal Adenoma Recurrence Due to Red Blood Cell Folate Level in the Post Folate Fortification Era: Results From the Adenoma Prevention With Celecoxib (APC) Trial

M1177 Risk of Colorectal Adenoma Recurrence Due to Red Blood Cell Folate Level in the Post Folate Fortification Era: Results From the Adenoma Prevention With Celecoxib (APC) Trial

Abstract 2831: Ornithine decarboxylase polymorphisms and risk of colorectal adenoma

Abstract Introduction: In a recent randomized trial the combination of difluoromethylornithine (DFMO) and the NSAID sulindac was remarkably effective in reducing the risk of colorectal adenoma recurrence. DFMO is a specific inhibitor of ornithine decarboxylase (ODC), which catalyzes the first step in polyamine synthesis. ODC and polyamines, which regulate cell growth and survival, have long been associated with colon carcinogenesis. In previous studies a SNP in the ODC promoter region was associated with risk of adenoma and response to aspirin treatment. The objective of this research was to perform a more comprehensive investigation of the association of adenoma risk with common genetic variation across the entire ODC gene, including potential upstream and downstream regulatory regions. Methods: We investigated the association between genetic variation in the ODC gene and risk of adenoma recurrence among a cohort of 920 participants in the Aspirin/Folate Polyp Prevention Study. Using the Sequenom platform, we genotyped 29 SNPs within a 23kb region. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs) adjusted for age and gender. Interactions terms were used to test whether ODC genotype modified the protective effect of aspirin treatment. Results: As gene frequencies for 26 of the 29 SNPs varied significantly by race/ethnicity, analyses were limited to whites only (86%). There were 7 SNPs associated with increased risk and 3 with decreased risk of adenoma recurrence (see table). In addition, at least three SNPs without any main effect modified the effect of aspirin treatment: rs1405948 (P for interaction=0.048), rs28362422 (P=0.043), and rs4669584 (P=0.050). Conclusion: Our findings suggest that common genetic variation throughout the ODC gene and adjacent regulatory regions influence risk of adenoma recurrence as well as efficacy of aspirin treatment.Association of ODC polymorphisms with adenoma riskSNPRR95% CIP-valueModelMAFLocationrs23575511.231.06-1.440.008dominant0.345′ flankingrs23026141.371.08-1.740.009dominant0.04exon 2rs37526611.351.06-1.720.017dominant0.04intron 5rs10495001.381.08-1.750.009dominant0.04exon 12rs8181620.700.52-0.940.019recessive0.303′ flankingrs109296691.251.06-1.480.009dominant0.113′ flankingrs24634630.760.62-0.930.009recessive0.443′ flankingrs24304201.251.08-1.460.004dominant0.323′ flankingrs116949111.341.13-1.590.001dominant0.113′ flankingrs130009160.770.63-0.040.009recessive0.453′ flanking Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2831.

Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence--data from a randomized clinical trial.

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the production of prostaglandins, potent mediators of inflammation. Chronic inflammation plays an important role in the development and progression of colorectal cancer. Aspirin inhibits COX-2 activity and lowers the risk for colorectal adenomas and cancer. We investigated whether common genetic variation in COX-2 influenced risk for colorectal adenoma recurrence among 979 participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or aspirin and followed for 3 years for the occurrence of new adenomas. Of these participants, 44.2% developed at least one new adenoma during follow-up. Adjusted relative risks and 95% confidence intervals (95% CI) were calculated to test the association between genetic variation at six COX-2 single-nucleotide polymorphisms and adenoma occurrence and interaction with aspirin treatment. Two single-nucleotide polymorphisms were significantly associated with increased adenoma recurrence: for rs5277, homozygous carriers of the minor C allele had a 51% increased risk compared with GG homozygotes (relative risk, 1.51; 95% CI, 1.01-2.25), and for rs4648310, heterozygous carriers of the minor G allele had a 37% increased risk compared with AA homozygotes (relative risk, 1.37; 95% CI, 1.05-1.79). (There were no minor allele homozygotes.) In stratified analyses, there was suggestive evidence that rs4648319 modified the effect of aspirin. These results support the hypothesis that COX-2 plays a role in the etiology of colon cancer and may be a target for aspirin chemoprevention and warrant further investigation in other colorectal adenoma and cancer populations.

Could recommendations about aspirin prophylaxis enhance colorectal cancer screening programmes?

A paper published in the March 2004 edition of the European Journal of Public Health evaluated the evidence on aspirin and colorectal cancer using the nine causality criteria originally put forward by Sir Austin Bradford-Hill in 1965.1 Using this framework, the evidence that aspirin might reduce the risk of colorectal cancer by 20–30% was evaluated as ‘suggestive’. Colorectal adenomas are putative precursors of sporadic colorectal cancer. A meta-analysis of four randomized controlled trials has provided evidence that aspirin, perhaps even in low doses, reduces the risk of colorectal adenoma recurrence by ∼30%.2 This meta-analysis provides further suggestive evidence that aspirin might exert chemopreventive benefits against colorectal carcinogenesis and thus reduce the risk of cancer developing. Adenomas, however, only offer a proxy measure of cancer risk and there are uncertainties and questions remaining about the evidence on aspirin and colorectal cancer chemoprevention.3 This includes the optimum dose, duration and frequency of aspirin that might achieve chemoprevention.3 These are important questions since aspirin increases the risk of undesirable effects, such as major bleeding. The consequences of these undesirable effects can be serious, even fatal in rare cases. …

Does the Location of Adenoma At Baseline Predict the Location of Subsequent Recurrence? Evidence from the Polyp Prevention Trial

Background: Studies have suggested possible biological differences between proximal and distal colon neoplasia. There is limited prospective data on the role of location in colorectal carcinogenesis. Aim: To examine whether the baseline location of adenoma predict the location of subsequent recurrence. Methods: The Polyp Prevention Trial was a 4-year, multicenter, randomized control trial which evaluated the effect of a low fat, high fiber, fruits and vegetable diet on the risk of colorectal adenoma recurrence. A total of 1,864 participants had complete information on the location of their baseline adenomas and completed the trial. We examined the association between baseline adenoma location on subsequent distal (rectosigmoid to splenic flexure) and proximal (transverse colon to cecum) adenoma recurrence. We used multinomial regression models to estimate the Relative Risks (RR) and 95% confidence intervals (CI). Results: A total of 1,131 (60.7%) subjects did not have adenoma recurrence while 733 (39.3%) subjects had adenoma recurrence (228 distal only; 369 proximal only; and 136 in both distal and proximal colon). Overall, given adenoma recurrence, there was a tendency towards a proximal shift (Table). In multivariable analysis with adjustment for age, sex, body mass index, family history of colorectal cancer and use of non-steroidal anti-inflammatory drugs, subjects with only proximal adenoma at baseline were less likely to have only distal adenoma recurrence (RR = 0.69; 95% CI: 0.47-1.00), but were more likely to have proximal adenoma recurrence (RR = 1.58; 95% CI: 1.20-2.09). Participants with proximal and distal adenomas at baseline were more likely to have adenoma recurrence in both locations: (RR = 1.61; 95% CI: 1.11-2.33) for distal only and (RR = 2.11; 95% CI: 1.53-2.90) for proximal only adenoma recurrence. Conclusions: Our study suggests a proximal shift of metachronous adenomas and subjects with adenomas in both distal and proximal colon are at the highest risk of adenoma recurrence.

Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial

Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial